CA2025731A1 - Phenylalkyl amine derivatives having antiischaemic activity - Google Patents

Phenylalkyl amine derivatives having antiischaemic activity

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Publication number
CA2025731A1
CA2025731A1 CA002025731A CA2025731A CA2025731A1 CA 2025731 A1 CA2025731 A1 CA 2025731A1 CA 002025731 A CA002025731 A CA 002025731A CA 2025731 A CA2025731 A CA 2025731A CA 2025731 A1 CA2025731 A1 CA 2025731A1
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Prior art keywords
group
atoms
alkyl
alkenyl
alkynyl
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French (fr)
Inventor
Donald T. Witiak
Ineke Van Wijngaarden
Raghunathan V. Nair
Josephus H. M. Lange
Jacobus A. J. Den Hartog
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Duphar International Research BV
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/58—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/64—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D319/18—Ethylenedioxybenzenes, not substituted on the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D321/00—Heterocyclic compounds containing rings having two oxygen atoms as the only ring hetero atoms, not provided for by groups C07D317/00 - C07D319/00
    • C07D321/02—Seven-membered rings
    • C07D321/10—Seven-membered rings condensed with carbocyclic rings or ring systems

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Cardiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pyridine Compounds (AREA)
  • Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Abstract The invention relates to compounds having anti-ischaemic activity of the formula (1) wherein:
-R1 + R2 together form an alkylene group having 1-3 C-atoms which may be substituted with one or more alkyl group(s) having 1-3 C-atoms;
-Z is methylene optionally substituted with one or two alkyl group(s) having 1-3 C-atoms, or with one phenyl group or phenylalkyl group with 1-3 C-atoms in the alkyl group, which phenyl groups may be substituted with a group (R6)p wherein R6 is halogen, hydroxyl alkyl or hydroxyalkyl having 1-5 C-atoms, alkoxy having 1-3 C-atoms, S-alkyl, S(O)-alkyl or S(O)2-alkyl having 1-3 C-atoms, amino, mono- or dialkylamino having 1-3 C-atoms per alkyl group, trifluoromethyl, trifluoromethoxy, a sulphonylamido group SO2NHR or a carbalkoxy group COOR wherein R is alkyl having 1-4 C-atoms, the group COOH, SO3H,COHN2, the amidino group or cyano group, and p has the value 0-3;
-R3 and R4 independent of each other represent hydrogen, alkyl having 1-10 C-atoms, alkenyl or alkynyl having 3-10 C-atoms, cycloalkyl having 3-8 C atoms, cycloalkyl-alkyl having 3-8 ring atoms and 1-5 C-atoms in the alkyl group, phenylalkyl or heteroaryl-alkyl having 1-5 C-atoms in the alkyl group, phenylalkenyl, heteroaryl-alkenyl, phenylalkynyl or heteroaryl-alkynyl group having 3-5 C-atoms in the alkenyl group or alkynyl group, which groups R3 and R4 may be substituted with a group (R6)p wherein R6 and p have the above mentioned meanings, or wherein R3+R4 together with the nitrogen atom form a saturated or unsaturated heterocyclic group of 5-7 ring atoms, which may contain a second hetero-atom from the group consisting of oxygen, sulphur and nitrogen, which ring may be substituted with a group (R6)p wherein R6 and p have the above mentioned meanings, or with phenylalkyl, phenylalkenyl, thienylalkenyl, pyridinylalkenyl, phenylalkynyl, thienylalkynyl or pyridinylalXynyl having at most 3 C-atoms in the alkyl, alkenyl or alkynyl part, which groups may be substituted with a group (R6)p wherein R6 and p have the above-mentioned meanings, or which ring may be annelated with a phenyl group:
-R5 is alkyl having 1-12 C-atoms, alkenyl or alkynyl having 3-12 C-atoms, cycloalkyl having 3-8 C-atoms, cycloalkyl-alkyl having 3-8 ring atoms and 1-5 C-atoms in the alkyl group, phenylalkyl or heteroaryl-alkyl having 1-5 C-atoms in the alkyl sub-group, phenylalkenyl, heteroaryl-alkenyl, phenylalkynyl or heteroaryl alkynyl having 3-5 C atoms in the alkenyl sub-group or alkynyl sub-group, which groups may be substituted with a group (R6)p, wherein R6 and p have the above-mentioned meanings, and which alkyl sub-groups, alkenyl sub-groups and alkynyl sub-groups may contain a group -O-, -S- or CO, or a pharmacologically acceptable salt thereof.

Description

Phenylalkyl amine derivatives havinq~ ischaemic activity The inventioF~ relates to a group o~ new phenylalkyl amine derivatives having interesting anti-ischaemic activity, to a method of preparing said compounds, and to pharmaceutical compositions comprising at least one of these compounds as the active component.
There is an increasing clinical interest in an ef~ective pharmalogical symptomatic treatm~nt for cersbral a~d peripheral ischaemic diseases. In patients suffering ~rom these diseases the impaired blood supply causes an inadequate delivery of oxygen and other nutrients to the tissue as well as a diminished removal of metabolic waste products resulting in structural injury and functional deterioration.

The object of the present invention is to provide active compounds with anti-ischaemic properties.

It has been found surprisingly that compounds of formula 1 K,O Z N ~

wherein -Rl + R2 together form an alkylene group having 1-3 C-atoms which may be substituted with one or more alkyl group(s) having 1-3 C-atoms;
-Z is methylene optionally ~ubstituted with one or two alkyl group(s) having 1-3 C-atoms, or with one phenyl group or phenylalkyl group with 1-3 C-atoms in the alkyl group, which phenyl groups may be substituted .
,: .

:
, ~ .
, - \
~ r~
with a group (R6)p wherein R6 is halogen, hydroxy, alkyl or hydroxyalkyl having 1-5 C-atoms, alkoxy having ` 1-3 C-atoms, S-alkyl, S(O)-alkyl or S(O)2-alkyl having 1-3 C-atoms, amino, mono- or dialkylamino having 1-3 C-: 5 atoms per alkyl group, trifluoromethyl, tri~luoromethoxy, a sulphonylamido group SO2NHR or a carbalkoxy group COOR wherein R is alkyl having 1-4 C-atoms, tha group COOH, SO3H,CO~N2, the amidino group or cyano group, and ~ has the vaLue 0-3;
-R3 and R4 independent of each other represent hydrogen, alkyl having 1-10 C-atoms, alkenyl or alkynyl having 3-10 C atoms, cycloalkyl having 3-8 C-atom~/ cycloalkyl-alkyl having 3-~ ring atoms and 1-5 C-atoms in the alkyl group, phenylalkyl or heteroaryl-alkyl having 1-5 C-atoms in the alkyl group, phenylalkenyl, heteroaryl-alkenyl, phenylalkynyl or heteroaryl-alkynyl group having 3-5 C-atoms in the alkenyl group or alkynyl group, which groups R3 and R4 may be substituted with a group ~R6)p wherein R6 and p have the above mentioned meanings, or wherein R3+R~ together with the nitrogen atom ~orm a saturated or unsaturated heterocyclic group of 5-7 ring atoms, which may contain a second hetero-atom from the group consisting of oxygen, ulphur and ni'rogen, which ring may be substituted with a group ~R6)p wherein R6 and p have:the above mentioned meanings, or with phenylalkyl, phenylalkenyl, thienylalkenyl, pyridinylalkenyl, phenylalkynyl, thienylallcynyl or pyridinylalkynyl having at most ~ C-atoms in the alkyl, alkenyl or alkynyl part, which groups may be substituted with a group (R6)p wherein R6 and ~ have the above-mentioned meanings, or which ring may be annelated with a phenyl group;
-R5 is alkyl having 1-12 C atoms, alkenyl or alkynyl having ~ ~ . . ... .

' : ~, ; , "

, .

~3~ 73~
3-12 C-atoms, cycloalkyl having 3-8 C-atoms, cycloalkyl-alkyl having 3-8 ring atoms and 1-5 C~atoms in the alkyl group, phenylalkyl or hsteroaryl alkyl having 1-5 C-atoms in the alkyl sub~group, phenylalkenyl, heteroaryl-alkenyl, phenylalkynyl or heteroaryl-alkynyl having 3-5 C-atoms in the alkenyl sub-group or alkynyl sub-group, whiah groups may be sub~tituted with a group (R6)p, wherein R6 and ~ have the above-mentioned meanings, and which alkyl sub-groups, alkenyl sub-groups and alkynyl sub-groups may contain a group -O-, S- or CO, prodrugs and pharmaceutically acceptahle acid addition salts thereof have interesting and valuabl2 anti-ischaemic properties.
Prodrugs are derivatives of these compounds which as such are inactive, from which, after splitting off an easily removable group, for example an ester group or an ether group, an active compound of formula 1 is obtained.
Suitable acids with which suitable addition salts can be formed are, for example, hydrochloric acid, sulphuric acid, phosphoric acid, nitric acid, and organic acid~ like citric acid, fumaric acid, maleic acid, tartaric acid, acetlc acid, : benzoic acid, p-toluene sulphonic acid, methane sulphonic acid, etc.

one or more c~ntres of chirality may be present in the compounds haYing formula l. The invention relates both to racemates and the individual isomers of the compounds having formula l.

The anti-ischaemic activity of the compounds has been determined by means of the in vivo hypoharic hypoxia test , ~ ~

. ~: , " ~ , .. :

J''~ J 3 and the in vitro cardiomyocytes test. The~e tests were used to characterize substances with cerebro- and/or peripheral-protective activity.
5 1) Hypobaric activi~y in vlvo Cerebro-protective activity was determined by measuring the prolongation of the survival time of conscious mice under hypobaric conditions.
Groups of 3 overnight fasted male NMRI mice tl5-20 g) are dosed ip (30 mg/kg), 30 minutes before being placed in a chamber at hypobaric pressure of 200 mBar. The prolongation of the survival time is expressed in percentage incrsase in respiration time, compared to that of the placebo traated control group.
2) Cardiomyocytes in vitro:
Cyto-protective properti~s were determined in an in vitro model using isolated calcium tolerant cardiomyocytes according to L. Verdonk et al (Lifs Sciences, v01.38, (1986) 765-772).
Cardiomyocytes were isolated from male Wistar rat hearts.
Rod shaped cells were incubated with the compound to be tested for 30 min. Injury was induced by e.g. veratrine ~100/ug/ml) or by hypoxia upon which the cells became rounded unless protected by the compound. After 20 min. the remaining rod-shaped cells were counted and the protecting efficacy of the compound was determined.

The compounds having formula 1, wherein the symbols have the above-mentioned meaning are new compounds which can be prepared according to methods known per se.

For example compounds having formula 1 can be obtained by ' ' .
"

2 ~3 67 5DlR 0444 first preparing a compound having formula 2 ~,O o ~
~~Z--N'~ (2~

wherein Rl-R4 and Z have the above mentioned meanings, by reacting a compound o~ the formula 3 ~I
~oJ~J
(3) with a compound o~ the formula R3R4NH and an aldehyde of the formula R7CHO, in which formulae Rl-R4 have the above mentioned meaning and R7 is hydrogen, alkyl having 1-3 C-atoms, phenyl or phenylalkyl, which phenyl groups may be substituted with a group (R6~p wherein R6 and p have the above mentioned meanings. This so-called Mannich-reaction is preferably carried out in an inert organic solvent, such as ethanol or acetonitrile.

The starting compound6 o~ formula 3 are known or can be obtained analogously to known compounds.
The so-obtained compounds of ~ormula 2 can ke converted into the corresponding compounds of formula 1 whierein R5 has the above mentioned meanings by means of a reaction with a .~ .. . .
,, compound of the formula R5-X, wherein X is a so-called leaving group, for example halogen. This reaction is preferably carrled out in an inext solvent ~uch as dimethylsulphoxide (DMSO), N,N-d:Lmethyl~ormamide ~DMF) and the like, in the presence of a 6uitable base such as sodium hydride or potas~ium tert-butoxide and the like. Sometimes the addition of sodium iodide is desirable. The reaction may be carried out at somewhat elevated temperatures.

Compounds of the formula 1 wherein R4 is hydrogen can be obtained by the reductive amination reaction o~ a compound of formula 4 ~J C; ~
~ O ~ C - ~ (4) with an amina of the formula R3NH2, in which formulae Rl-R3 and R5 have the meanings given in ~`ormula 1, and R7 has the meaning given above. Addition of an acid ~atalyst may be desirable to enhance the reaction rate. The reaction is preferably carried out in an inert solvent. Removal of water formed during the reaction is preferably carried out during the amination step by means of azeotropic distillation with an aromatIc solvent, for example benzene or toluene. The reductive step of this process can be carried out with a suitable reducing agent such as LiAlH4 in an inert solvent, for example tetrahydrofuran or diethyl ether, or by other known reductive amination methods lsee for example Russ.
Chem. Rev. 49, 14 (1980), or Synthesis, 135 (197~)).

Starting compounds of the formula 4 are known (J.Chem.Soc.

' 2 ~J~
Perkin I, 305, (1974); Synth.Commun. Io, 9, (1980)), or can be prep~red in a similar manner.

The so-obtained compounds of formula 1, wherein R4 i6 hydrogen can be converted into the corre ponding compounds whPrein R4 has another meaning by reductlve alkylation with a suitable aldehyde in the presence of a reducing agent such as sodium cyanoborohydride in an inert solvent.

The above de~cribed reductive amination of a compound o~
formula 4 can also be carried out with a secondary amine of the ~ormula R3R4NH, leading directly to the desired end products of ~ormula 1.

The invention will be further illustrated by means o~ the following examples.

Example I
5-NlN-diethylaminomethyl-6-hydroxY-1,3-be,n,,zodioxole To a stirred solution o~ 5-hydroxy-1,3-benzodioxole (5.0 g, 36.2 mmol) and diethylamine (2.9 g, 39.7 mmol) in ethanol (25 ml~ was added dropwise 37% aqueous formaldehyde (3.2 g, 39.5 mmol). The reaction mixture was stirred at room temperature for 4 hours and evaporated in vacuo. The remaining oil (7.4 g) was crystallized from methanol;
melting point 52-54C (compound no.l).
In a similar manner the compounds of formula 2 wherein Z and Rl-R4 have the meaning indicated in table A were prepared - , ., ;

, , :

, ~f~ ~J l~i~
Table A

_ , _ .
No. Rl ~ R2 R3 (~) ~4 æ m.p.(C~
5 ~ ~ _ : __ _ . ~ 2 -(CH2)- -(CH2) 2 (~H2 ) 2- ~H2 86- B8 3 -(CH~)~ -(CH2)5- C~2 50- 51 4 -(CH2)- -(CH2)2N(~H3)(~H2)2- CH2 95- 97 -(CH2)~ -(cH2)2N(cH2cH2cH3)~r~2)2- CH2 oil 6 ~ (C~2 ) 2- C2H5 C2~5 CH2 oil - 7 -(CH2)2~ -(C~2)5 CH2 oil 8 -(C~2)- -(CH2)2N(cH(c6Hs)2)(cH2)2- CN2 160-161 g (C~2)- -(CH2)5- CH(C6Hs) 180(dec.), (HBr-salt) - 15 10 (CH2~-- H C2~5 CH(C6Hs) oil ___ . _ .. ~

Example II
5-N~N-diethylaminomsthyl-6-E~henylmethoxy-1~3-benzodioxo-le.HCl To a mixture of 5-N,N-diethylaminomethyl-6-hydroxy-1,3-benæodioxole (2.0 g, 9 mmol), sodium iodide (0.135 g, 0.9 mmol) and potassium-tert-butoxide (lol9 g, 10.5 mmol) in - DMSO (30 ml) wa~ added benzyl bromide (1.54 g, 9 mmol). The stirred mixture was heated at 80C for 3 hours. Thereafter, the mixture wa~ allowed to attain room temperature, water was added and the resulting solution was extracted with dichloromethane, washed with a 2N sodium hydroxide ~olution and brine respectively, dried over ~gS04, filtered and evaporated in vacuo. Ths obtained brown oil (3.7 g) was : purified by ~la~h chromatography (silica gel, dichlorometha- ~.
ne/methanol/ammonia(25%)= 95/4.5/0.5) to give pure 5-N,N-diethylaminomethyl-6-phenylmethoxy-1,3-benzodioxole (2.0 g, .

. ~ '' ' ' ' ' ' , .

C~

g DIR 0444 yield 71~). A mixture o~ isopropanol and diethyl ether wa6 added to the obtained produat, and the resultiny solution was saturated with gaseous hydrogen chloride. After evaporation o~ the solvents in vacuo 5-N,N-diethylaminome-th~l-6-phenylmethoxy-1,3-henzodioxole.HCl (1.4 g, yield 45%) was obtained as a white solid; m.p. 122-123C ~compound no.
11) .
In a similar manner the compounds of ~ormula 1 wherein Z
and Rl-R5 have the meaning indicated in table 3 were prepared:

,:: ~ :., ,.:
::...... :
, .,. ~, :
:~ .,. ,:
; !: ' Ir~ ~J ~

_ ....
C~ O ~ y q ~ q ~ 0 ~ C~ O 'I ~ O I
_ . ~

;~ O ~ 00 ~ -~ :

+

~ ~ O ~I t`J 10 ~5) ~ a~ ~ o _I

:

v~

--o ~ ~ ) a~ o 40 ~
~ ~ o ~ ,~ o b _ . ~ .. .. .

.~

-- -- ' -- -- -- ----- T~ ' .. .... _._.. _ _______.. _______._________ ~

,....... ._ _ _ ~ _ , ~ o ~
l ~
+
- -: - - - -o ~ ~ o 1~ 0 a~ o , I ~ t~ o ~ co ~ o ~l N

:' " ~ ~ ' . ''`' ' " ' ' ~ ~3 ?J '~J "~ 3 fll.

_. ._ C~ o ~ ~ o ,1 ,~ o ~ ~ ~ ~ ~ .'''' ~ C~ o l ~ ~3 .~.
_ _ .~ .~ l .
,~
_ _ _ _ ......

~ ~ _ 1- _ $~
~ ~ o o~ oF
~ C)~ _ U U U
__~

+ ~ ~.

æ
_ _ ~ ...
I i ' ' ' ' I I I I ~ I
+ ~ _ _ ~ ~ ~ ~ ~ ~ + ~
Z '~ ~ ~ ~ ~
_ . _ _ .

o ~ ~ In ~ t` OD ~n O ~1 O ~ ~ U~
. _ u~ D . ~

' :
.
', , ' ~ ' .:

v o ~ ~ ~ In ~ OD O O
3 d~
_.~ ~ I
C~ r~ I~ ~D ~ ~ ~ 00 . ~ ~ In ~1 ~ ~1 OD ~ a ~ ~ I
_ _ _, ~ ' ' ~ , . _ _l ~ ~ ,~ ,~1 ~ ~ ~ ~
D ~ :
æ ~
~1 _ ~1 ~
~ : ~
~ ~ ~ -c~
~: g ~ g ~
~ r ~ `:
j~ ~
_ :~
æ
~ ..
+
Z
_ ~
I` CO ~ O ~ In ~:
'. ~ I` t~ I` ~ r~ I`
~_~
::~

: ~ r Pbf ~

Exam~le III
2-~N,N-diethylaminomethyl~-4,5~methylenedioxyphenyl-n-butyrate.HCl A mixture of 5-N,N-diethylaminomethyl-6-hydroxy-1,3-benzodi-oxole (3.0 g, 13.5 mmol), n-butyric anhydride (2.15 g, 13.6 mmol) and a drop of concentrated sulphuric acid was stirred at room temperatur~ for 15 minutes. Crushed ice was added to the clear solution. The pH of the solution was made alkaline (pH= 10-11) by means of a 10% NaOH solution. The mixture was extracted with diethyl ether and the combined ether extract wa~ washed with water, dried over Na2S04 and evaporated under reduced pressure. The resulting oil was dis~olved in diethyl ether and saturated with gaseous hydrochloric acid. The precipitated 2~(N,N-diethylaminomethyl)-4,5-methylene-dioxyphenyl-n-butyrate.HCl (compound no. 62) was filtered off and recrystallized from methanol/diethyl ether; m.p. 126-128C.

In a similar manner the compounds having ~ormula 1 wherein Z
is methylene and Rl-R5 have the meaning mentioned in table C
were obtained.

Example IV
5-N-(2~ henylethyl)aminomethyl-6-phenylmethoxy-1,3-_nzodioxole.HCl To a solution o~ 6-benzyloxy-3,4-methylenedioxybenxaldehyde (2.0 g, 7.~ mmol3 in benzenP (75 ml) were added phenethylamine (0.94 g, 7.8 mmol) and a catalytic amount of p-toluenesulphonic acid. The reaction mixture was heated at reflux temperature overnight using a Dean-Stark trap. The reaction mixture was cooled to xoom temperature and evapora-tad in vacuo. The residue was dissolved in dry THF, and : ' .

, ~s~

lithiumaluminium hydride (0.6 g, 16 mmol) was ~dded. Th~
mixture was heated at reflux temperature for 20 hours under nitrogen and then cooled to room kemperature. Excess LiAlH4 was decomposed by cautious addition of Na2SO~.10 H2O. The solid was filtered off and washad with two portion of hot tetrahydrofuran. The combined THF solution was evaporated under reduced pressure to give a yellow oil. The oil was dissolved in isopropanol/diethyl ether and saturated with gaseous hydrochloride. The precipitated 5-N-(2-phenylethyl)-aminomethyl-6-phenylmethoxy-1,3~benzoAioxole.HCl (compound no. 66) was filtered o~f and recrystallized from ethyl aceta-te; melting point 188-lg0C.

In a similar manner compounds of formula 1 wherein Z is methylene and Rl-R5 have the meaning given in table D were obtained.

Example V
5-N-r2-(3,4-dimethoxyphenyl)ethyl~-N-methyl-aminomethyl-6-phenylmethoxy-1l3-ben~odioxole.
Sodium cyanoborohydride ( 0.34 g, 5.4 mmol) was added to a solution of 5-N-[2-(3,4-dimethoxyphenyl)ethyl]aminomethyl-6-phenylmethoxy-1,3-benzodioxole (1.42 g, 3.37 mmol) and aqueous formaldehyde (37~ solution, 1~25 ml, 15.4 mmol) in acetonitrile (10 ml). The reaction mixture was stirred for 20 minutes at room temperature. The reaction mixture was made neutral by dropwlse addition of glacial acetic acid. Stirring was continued for 5 hours. The solvent was removed under reduced pressure and ~he residue was partitioned between 2N
potassium hydroxide solution 125 ml) and diethyl ether (25 ml). The aqueous layer was further extracted with two portions oP diethyl ether and the combined organic extract was washed with 0.5N KOH solution and with water. The ether `" 2~7~

solution was extracted with 10% hydrogen chloride solution.
The combined aqueous extract was made alkaline with sodium hydroxide pellets and the solution was extracted with diethyl ether. The combined diethyl ether ~sxtract was washed with water, dried over Na2S04 and ev~porated under reduced pressure to give 1.03 g (yield 70%) of 5-N-[2-(3,4-dime-thoxyphenyl)ethyl]-N-methyl-aminomethyl-6-phenylmethoxy 1,3-benæodioxole (compound no. 76); melting point 7~-~0C.

In a similar manner compounds having ~ormula 1, wherein Z and Rl-R5 have the meanings given in table E were obtained.

, ~ ~ 2 ~ 7 r J ~

_ _ C~ o ~
o ~o _~
~, ' s _ :' ~;

:~

- , . . . - ., , ~ . . ~ . . , . , ~ .

Claims (7)

1. Compounds having anti-ischaemic activity of the formula (1) wherein:
-R1 + R2 together form an alkylene group having 1-3 C-atoms which may be substituted with one or more alkyl group(s) having 1-3 C-atoms;
-Z is methylene optionally substituted with one or two alkyl group(s) having 1-3 C-atoms, or with one phenyl group or phenylalkyl group with 1-3 C-atoms in the alkyl group, which phenyl groups may be substituted with a group (R6)p wherein R6 is halogen, hydroxy, alkyl or hydroxyalkyl having 1-5 C-atoms, alkoxy having 1-3 C-atoms, S-alkyl, S(O)-alkyl or S(O)2-alkyl having 1-3 C-atoms, amino, mono- or dialkylamino having 1-3 C-atoms per alkyl group, trifluoromethyl, trifluoromethoxy, a sulphonylamido group SO2NHR or a carbalkoxy group COOR wherein R is alkyl having 1-4 C-atoms, the group COOH, SO3H,CONH2, the amidino group or cyano group, and p has the value 0-3;
-R3 and R4 independent of each other represent hydrogen, alkyl having 1-10 C-atoms, alkenyl or alkynyl having 3-10 C-atoms, cycloalkyl having 3-8 C-atoms, cycloalkyl-alkyl having 3-8 ring atoms and 1-5 C-atoms in the alkyl group, phenylalkyl or heteroaryl-alkyl having 1-5 C-atoms in the alkyl group, phenylalkenyl, heteroaryl-alkenyl, phenylalkynyl or heteroaryl-alkynyl group having 3-5 C-atoms in the alkenyl group or alkynyl group, which groups R3 and R4 may be substituted with a group (R6)p wherein R6 and p have the above mentioned meanings, or wherein R3+R4 together with the nitrogen atom form a saturated or unsaturated heterocyclic group of 5-7 ring atoms, which may contain a second hetero-atom from the group consisting of oxygen sulphur and nitrogen, which ring may be substituted with a group (R6)p wherein R6 and p have the above mentioned meaning, or with phenylalkyl, phenylalkenyl, thienylalkenyl, pyridinylalkenyl, phenylalkynyl, thienylalkynyl or pyridinylalkynyl having at most 3 C-atoms in the alkyl, alkenyl or alkynyl part, which groups may be substituted with a group (R6)p wherein R6 and p have. the above-mentioned meanings, or which ring may be annelated with a phenyl group;
-R5 is alkyl having 1-12 C-atoms, alkenyl or alkynyl having 3-12 C-atoms, cycloalkyl having 3-8 C-atoms, cycloalkyl-alkyl having 3-8 ring atoms and 1-5 C-atoms in the alkyl group, phenylalkyl or heteroaryl-alkyl having 1-5 C-atoms in the alkyl sub-group, phenylalkenyl, heteroaryl-alkenyl, phenylalkynyl or heteroaryl-alkynyl having 3-5 C-atoms in the alkenyl sub-group or alkynyl sub-group, which groups may be substituted with a group (R6)p, wherein R6 and p have the above-mentioned meanings, and which alkyl sub-groups, alkenyl sub-groups and alkynyl sub-groups may contain a group -O- , -S- or CO, or a pharmacologically acceptable salt thereof.
2. A method of preparing phenylalkyl amine derivatives, characterized in that compounds having formula 1, wherein Z
and R1-R5 have the meanings given in claim 1 are prepared by reacting a compound having formula 2 (2) with a compound of the formula R5-X wherein R5 has the meaning given in claim 1 and X is a leaving group.
3. A method as claimed in claim 2, characterized in that compounds having formula 1 wherein Z and R1-R5 have the meanings given in claim 1, are prepared by reacting a compound of formula 4 (4) wherein R7 is hydrogen, alkyl with 1-3 C-atoms, phenyl or phenyalkyl, which phenyl groups may be substituted with a group (R6)p wherein R6 and p have the meanings given in claim 1, with an amine of the formula R3NH2 and optionally converting the obtained compound wherein R4 is hydrogen into a compound wherein R4 has one of the other meanings given in claim 1 by means of reductive alkylation.
4. Compositions having anti-ischaemic activity which comprise at least one compound as claimed in claim 1 as active component, together with a suitable diluent or carrier.
5. A method of preparing compositions as claimed in claim 4, characterized in that a compound of formula 1 wherein the symbols have the meaning mentioned in claim 1, or a salt thereof, is brought into a form suitable for admini-stration.
6. Use of a compound as claimed in claim 1 for treating ischaemia.
7. A commercial package containing as active pharmaceuti-cal ingredient a compound as claimed in claim 1, together with instructions for the use thereof in treating ischaemia.
CA002025731A 1989-09-22 1990-09-19 Phenylalkyl amine derivatives having antiischaemic activity Abandoned CA2025731A1 (en)

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AU646926B2 (en) * 1991-03-20 1994-03-10 Duphar International Research B.V. Alkylenedioxyphenyl ether derivatives having anti-ischaemic, memory enhancing and anti-convulsive activity
DE69227596T2 (en) * 1991-10-04 1999-04-08 Taisho Pharmaceutical Co Ltd ALKOXYPHENYLALKYLAMINE DERIVATIVE
ATE193204T1 (en) * 1993-09-07 2000-06-15 Taisho Pharmaceutical Co Ltd PREPARATION FOR TREATING DRUG DEPENDENCE
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US5482523A (en) * 1994-11-02 1996-01-09 Chevron Chemical Company Mannich condensation products of poly(oxyalkylene) hydroxyaromatic ethers and fuel compositions containing the same
WO1997000238A1 (en) * 1995-06-14 1997-01-03 Taisho Pharmaceutical Co., Ltd. Optically active substituted phenylalkylamine derivatives
US20090012157A1 (en) 2006-02-06 2009-01-08 Sears Barry D Sesamol Derivatives as Novel Inhibitors of Arachidonic Acid Formation

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